PROJECT SUMMARY This application focuses on investigating signals in the subventricular zone (SVZ) that regulate oligodendrocyte (OL) development in the healthy and injured brain. OLs arise from neural stem cells in the SVZ and produce the myelin sheaths that insulate neuronal axons, thus allowing proper synaptic transmission. Damage to or loss of OLs results in many neurological problems, as can be seen in multiple sclerosis and other neurodegenerative diseases. Therefore, identifying endogenous mechanisms that regulate OL development and repair in vivo may lead to new therapeutic targets for treating such conditions. Our previous studies found that the signaling peptide, Endothelin-1, delays OL maturation after demyelination of white matter in the rodent brain. This suggests that Endothelin-1 is a novel regulator of OL development in vivo. To test this hypothesis, the function of Endothelin-1 in the SVZ during normal development and after white matter injury will be determined. First, the mechanism of Endothelin-1 in the postnatal SVZ will be genetically dissected using conditional knockout mice and RNA sequencing. Then, using the lysolecithin model of demyelination and viral tracing, the role of SVZ-derived Endothelin-1 in OL regeneration will be defined.